Next to the heart disease, cancer is the major cause of death in the USA, causing over 500,000 fatalities annually. With present methods of treatment, one-third of these patients are cured with local surgery or radiation therapy; however, in the remaining cases a systemic approach of chemotherapy is required. At present, chemotherapy provides palliative rather than curative therapy for many forms of cancer resulting in temporary clearing of the symptoms and signs of cancer. Therefore, there is a critical need for the development of newer more potent and less toxic chemotherapeutic classes of drugs for the treatment of cancer. Several antibiotics such as doxorubicin, mitomycin, cordycepin, pentostatin and neplanocin, have been used as anticancer agents and/or as "lead structures" for the design of new compounds. Our approach to uncover new structural "leads" is to explore these antibiotics, especially nucleoside analogues, wherein the unique electronic properties in their chemical structure has resulted in their potent anticancer activity. For example in antibiotic neplanocin A, presence of a strategically placed double bond (pi electron cloud) in its carbocycle moiety is a structural feature important for its potent antitumnor activity. Using neplanocin as the "lead structure", we propose to design new aromatic carbocyclic neplanocin analogues wherein the cyclopentene carbocycle of neplanocin A is replaced with a rationally substituted double bond rich aryl ring (pi electron cloud rich) to mimic and strenghthen the required electronic properties for stronger binding to both target and nontarget macromolecules for improved therapeutic actions of the drug. To test this hypothesis, we propose to conduct the following studies: a) design and synthesize a series of rationally substituted aromatic neplanocin A analogues, c) evaluate them for in-vitro anticancer activity at the National Cancer Institute, and c) conduct the DNA binding studies to establish their mechanism of action. Preliminary studies on some designs proposed in this project have already yielded several compounds with anticancer properties. The information gained in this project will be valuable not only in determining the structure-activity-relationship (SAR) of this new class of compounds, but may also result in the development of new potent and selctive anticancer agents.